Temperature controlling device for aerosol drug delivery

ABSTRACT

A portable air temperature controlling device useful for warming air surrounding an aerosolized drug formulation is described. Warming the air of an aerosol makes it possible to reduce the size of aerosol particles produced by an aerosol generation device. Additionally, warming the air forces the size of the aerosol particles to be in the range required for systemic drug delivery independent of ambient conditions. Smaller particles can be more precisely targeted to different areas of the respiratory tract.

CROSS REFERENCES

This application is a continuation of U.S. application Ser. No.09/839,248 filed Apr. 20, 2001 U.S. Pat. No. 6,629,526 which is acontinuation of U.S. application Ser. No. 09/690,242 filed Oct. 16, 2000(now U.S. Pat. No. 6.263,872, issued Jul. 24, 2001, which is acontinuation of U.S. application Ser. No. 09/107,306 filed Jun. 30, 1998(now U.S. Pat. No. 6,131,570, issued Oct. 17, 2000) which is acontinuation-in-part of U.S. application Ser. No. 08/752,2946 filed Nov.21, 1996 (now U.S. Pat. No. 5,906,202 issued May 25, 1999) whichapplications and patents are incorporated herein by reference and towhich applications we claim priority under 35 U.S.C. §120.

FIELD OF THE INVENTION

This invention relates generally to portable devices and methods usefulfor optimizing the size distribution of a medical aerosol, and reducingthe amount of variability arising from variations in ambient conditions.More specifically, this invention relates to battery powered, portabledevices for controlling the temperature of air surrounding aerosolparticles of drugs and delivering the drug to a specific area of thelung.

BACKGROUND OF THE INVENTION

There are several known methods for the aerosolized delivery of drugs.In general, the methods include: (1) placing an aqueous formulationwithin a nebulizer device which by various mechanical means causes thedrug formulation to be aerosolized in a continuous stream which isinhaled by the patient; (2) dry powder inhalers which create a finepowder of the drug and aerosolize the powder in a dust form which isinhaled; (3) metered dose inhalers which dissolve or disperse the drugin a low boiling point propellant; and (4) more current devices such asthat disclosed within U.S. Pat. No. 5,660,166 issued Aug. 26, 1997 whichforce aqueous formulations through a nozzle to create an aerosol whichis inhaled by the patient.

In accordance with each of the known methods for aerosolizing a drug itis important to produce an aerosol which has particles within a desiredsize range, e.g. 0.5 to 12.0 microns and more preferably 1.0 to 3.5microns. In addition to producing small particles it is preferable toproduce particles which are relatively consistent in size, i.e. producean aerosol wherein a large percentage of the particles fall within thedesired size range. In addition, it is desirable to produce an aerosolwhich has the property that the key measures of aerosol quality, such asparticle size and dose emitted are not effected by ambient conditionssuch as temperature and or relative humidity. With any of the knownmethods for aerosol delivery of drugs there are difficulties withrespect to making the particles sufficiently small. Along with thesedifficulties there are difficulties with respect to creating particleswhich are relatively consistent in size. These difficulties areparticularly acute when attempting to provide For systemic delivery ofan aerosolized drug. Efficient systemic delivery requires that theaerosol be delivered deeply into the lung so that the drug canefficiently reach the air/blood exchange membranes in the lung andmigrate into the circulatory system.

Aerosol delivery to the lungs has been used for delivery of medicationfor local therapy (Graeser and Rowe, Journal of Allergy 6:415 1935). Thelarge surface area, thin epithelial layer, and highly vascularizednature of the peripheral lung (Taylor, Adv. Drug Deliv. Rev. 5:37 1990)also make it an attractive site for non-invasive systemic delivery.Unlike other avenues of non-invasive delivery such as trans-dermal,nasal, or buccal, the lung is designed as a portal of entry to thesystemic circulation. However, targeting the peripheral lung requirescareful control of the aerosol particle size and velocity distributions,in order to by pass the exquisitely evolved particle filtering andclearing functions of the bronchial airways.

Many authors have reported results of experiments or mathematical modelsshowing that micron sized particles are required for delivery to thelungs (c.f. Stahlhofen, Gebhart and Heyder, Am. Ind. Hyg. Assoc. J.41:385 1980, or Ferron, Kreyling and Haider, J. Aerosol Sci. 19:6111987). One example is the model of the Task Group on Lung Dynamics(Morrow et. al. Health Physics 12:173 1966). As FIG. 1 shows, under theassumptions of this model, particles of diameter less than ˜3.5 μm arerequired to avoid the oropharynx and bronchial airways. FIG. 1 mightsuggest that the maximum efficiency of deposition of drugs delivered tothe pulmonary region of the lung is limited to ˜60%. However, as can beseen in FIG. 2, efficiencies approaching 100% can be achieved byallowing the particles to settle gravitationally during a ten secondbreath hold (Byron, J. Pharm. Sci. 75:433 1986).

It has been demonstrated that ambient conditions can strongly effect theamount of aerosol particles less than 3.5 μm emitted from aerosolgeneration device. One example is the work of Phipps and Gonda (Chest97:1327-1332, 1990) showing that the amount of aerosol less than 3.5 μmdelivered by a aerosol drug delivery device changed from 33% to 73% whenthe relative humidity changed from 100% to 70%. Similar work with a drypowder (Hickey et al J. Pharm. Sci. 79, 1009-1011) demonstrated a chancein the amount of aerosol less than 3.5 μm from 9% to 42% when theambient relative humidity changed from 97% to 20%. These data aretabulated in Table 1.

TABLE 1 Effect of RH on Particle Size Distribution Aerosol T, ° C. R.H., % % <3.5 μm Isotonic Saline¹, Hudson Up-Draft 23-24° 100% 33%Isotonic Saline¹, Hudson Up-Draft 23-24° 65-75% 73% Fluorescein Powder²37 ± 0.1° 97 ± 1%  9% Fluorescein Powder² 37 ± 0.1° 20 ± 5% 42% ¹Phippsand Gonda, 1990 ²Hickey et al 1990

Many pharmaceutical compounds of a wide range of molecular weights arepotential candidates for systemic delivery via the lung. Small moleculesanalgesics such as morphine or fentanyl could be delivered to painpatients, e.g. cancer or post-operative patients. Morphine hasdemonstrated bioavailability when delivered via the lung (S. J. Farr, J.A. Schuster, P. M. Lloyd, L. J. Lloyd, J. K. Okikawa, and R. M.Rubsamen. In R. N. Dalby, P. R. Byron, and S. J. Farr (eds.),Respiratory Drug Deliver V. Interpharm Press, Inc., Buffalo Grove, 1996,175-185).

Potent peptide hormones are available for a variety of therapeuticindications. Leuprolide, for example, is a GNRH super-agonist useful inthe treatment of endometriosis and prostate cancer. Leuprolide also haspotential applications in the field of breast cancer management and thetreatment of precocious puberty. Calcitonin enhances metabolism and maybe a useful therapeutic agent for the management of osteoporosis, acommon complication of aging.

To treat conditions or diseases of the endocrine system, pharmaceuticalformulations containing potent peptide hormones are typicallyadministered by injection. Because the stomach presents a highly acidicenvironment, oral preparations of peptides are unstable and readilyhydrolyzed in the gastric environment. Currently, there are no oralpreparations of therapeutic peptide agents commercially available.

Both calcitonin and leuprolide can be administered nasally. (See Rizzatoet al., Curr. Ther. Res. 45:761-766, 1989.) Both drugs achieve bloodlevels when introduced into the nose from an aerosol spray device.However, experiments by Adjei et al. have shown that the bioavailabilityof leuprolide when administered intranasally is relatively low. However,an increase in the bioavailability of leuprolide can be obtained byadministering the drug into the lung. Intrapulmonary administration ofleuprolide has been shown to be an effective means of non-invasiveadministration of this drug (Adjei and Garren, Pharmaceutical Research,Vol. 7, No. 6, 1990).

Intrapulmonary administration of drugs has the advantage of utilizingthe large surface area available for drug absorption presented by lungtissue. This large surface area means that a relatively small amount ofdrug comes into contact with each square centimeter of lung parenchyma.This fact reduces the potential for tissue irritation by the drug anddrug formulation. Local irritation has been seen with nasal delivery ofinsulin and has been a problem for commercialization of nasalpreparations of that drug. It is a problem with peptide hormones thatthey are very potent with effects that are not immediately manifested.For example, therapy with leuprolide for prostate cancer does nottypically produce any acute clinical effects. Similarly, prophylaxisagainst osteoporosis with calcitonin will not produce any acute symptomsdiscernible to the patient. Therefore, administration of each dose ofthese drugs must be reliable and reproducible.

SUMMARY OF THE INVENTION

A portable, self-contained device useful for controlling the temperatureof the air surrounding an aerosolized drug formulation is provided. Thetemperature controlling device is comprised of a heating element(preferably in the form of a wire coil) which warms the air surroundingan aerosolized pharmaceutical formulation. The warming of the airresults in evaporating liquid carrier from aerosol particles of a liquidformulation, thereby obtaining a smaller, more uniform particle size.Alternatively, or in addition, the warming of the air can prevent orimpede the accumulation of water (which might condense from the air) onparticles of a liquid formulation or especially a dry powder. Becausewarming of ambient air will always result in a reduced relativehumidity, it is possible to ensure that only evaporation will occur, asdifferentiated from introducing aerosols into uncontrolled ambient air,where growth (i.e., condensation of water vapor on an aerosolizedparticle) or evaporation are generally possible. Thus the use of atemperature controller can reduce the dependence of particle size onambient conditions. The results of such make it possible to moreprecisely target areas of the respiratory tract by adjusting particlesize by warming the air.

To have practical utility any temperature controller to be used bypatients administering inhaled drugs must be small, efficient, andhighly portable. The invention preferably comprises a portable powersource such as a battery (e.g. 10 AA or similarly sized batteries orless), a control circuit, a temperature sensing means, a relay, and aheating element. These components are preferably combined with anaerosol generating means which is most preferably the type which movesformulation through holes. The air surrounding the aerosol particles ispreferably warmed to the extent that 50% or more of the carrier isevaporated away from the particles of an aqueous formulation. Morepreferably, the warming results in providing particles which aresubstantially dry—all free water being evaporated away. A very importantaspect of the invention is in a temperature controller which achievesthe desired effects while being powered only by a battery.

The heating element is preferably in the form of a wire coil of an alloycontaining some or all of: nickel, chromium, copper, and iron and havinga weight of about 5 grams (±4 grams) and a gauge of about 26 (±10gauge). Alternatively, the heating element may be in the form of astamped and/or folded metal sheet. Different types of heating elementscould be used provided they meet certain criteria. It must be possibleto heat the element with a portable battery source in a short period oftime, e.g. one minute or less. The element is preferably capable ofstoring sufficient energy to warm the air (e.g. 0.5 to 4 liters or moreof air) surrounding the aerosol particles sufficiently to evaporate allor most of the carrier, even at high ambient relative humidity. Theelement must also be capable of quickly releasing heat energy to theair, e.g. releasing 20 joules or more of energy in 10 seconds or less,preferably about 2.5 seconds or less. Stated functionally, the heatingelement must be able to absorb and then release heat energy in amountsufficient to control particle size for a useful aerosolized dose offormulation and that energy must be absorbed and released in a period oftime which is sufficiently short to be practically used duringaerosolized drug delivery.

Key to the functioning of the invention is the fact that the time for aheated object to cool off is significantly shorter in moving air than instill air. Thus it is possible to preheat the element over a period oftime of 10-60 seconds and store the heat for a similar period of time,and then deliver the heat into moving air in a period of time of 1-10seconds. The heating element must be able to deliver heat back to theair in a short period, e.g. a period which correspond to the length of apatient's inhalation.

The invention increases the number and types of pharmaceuticalformulations which can be administered efficiently and reproducibly byinhalation. More particularly, the invention makes it possible to inhaleformulations which are intended for systemic delivery, includingpeptides such as insulin and analogs of insulin (e.g., insulin lispro).This is done by increasing the reproducibility of dosing by adjustingparticle size to a consistent level in different surrounding humidities.Further, particular areas of the lung are targeted by (1) includingaerosolized formulation in precisely determined volumes of air, (2)warming air surrounding the aerosolized formulation so as to evaporatecarrier and reduce the particle size and/or to prevent water vapor inthe air from condensing on particles, (3) excluding aerosolizedformulation from other volumes of air delivered to the lung in order tocorrectly position an aerosol. Further, the heating means can be usedwith any type of means of generating an aerosol. More specifically, theheating means can be used with a nebulizer, a dry powder inhaler ormetered dose inhaler. However, the major benefits of the invention areobtained when used with a device which creates aerosolized particles bymoving liquid (aqueous or ethanolic) formulations through small holes tocreate particles (see U.S. Pat. No. 5,718,222 issued Feb. 17, 1998). Alltypes of nebulizers benefit from the invention by reducing variableeffects caused by the environment, e.g., changes in humidity.

The amount of energy added can be adjusted depending on factors such asthe desired particle size, the amount of the carrier to be evaporated,the water vapor content (humidity) and temperature of the surroundingair, the composition of the carrier, and the region of the lungtargeted.

To obtain reproducible, efficient systemic delivery it is desirable toget the aerosolized formulation deeply into the lung. This requires thedelivery of the formulation in aerosol particles of diameter less thanapproximately 3.5 μm. Direct generation of particles in this size rangecan be difficult, due to the large ratio of surface area to volume ofthese small particles. Energy may be added in an amount sufficient toevaporate all or substantially all the carrier from an aqueous aerosoland thereby provide particles of dry powdered drug or highlyconcentrated drug formulation to a patient which particles are (1)uniform in size regardless of the ambient humidity and temperature (2)preferably produced from a liquid formulation, and (3) smaller due tothe evaporation of the carrier.

A primary object of the invention is to provide an air temperaturecontrolling device comprised of a receptacle for holding aself-contained power source such as electric power cells forming abattery, a channel comprising an air flow path which includes an openinginto which air can be inhaled and a second opening into which air isdelivered and aerosol is generated, a heating element connected to theelectrical contacts of the receptacle and positioned in a manner suchthat air flowing by the heating element flows through the channel,wherein the device is a hand-held, self-contained device having a totalweight of one kilogram or less.

It is another object of the invention to provide such a device whereinthe heating element is comprised of an alloy containing copper,chromium, iron and/or nickel which heating element is preferably in theform of a wire having a gauge in the range of about 16 to 36 weighingapproximately 0.5 to 10 grams.

An important advantage of the invention is that the heating device canheat a sufficient amount of air so as to evaporate a sufficient amountof carrier on aerosolized particles to make the particles consistent insize and sufficiently small as to improve the repeatability andefficiency of drug delivery.

It is an object of this invention to provide a portable air temperaturecontrolling device able to warm the air surrounding the particles of anaerosolized drug formulation.

It is a further object of the invention to provide a drug deliverydevice containing such a heating element which is heated by a portable,self-contained energy source.

It is a further object of the invention to provide methods ofadministering aerosolized drug formulations in which the air surroundingthe aerosolized formulation is warmed using a portable air temperaturecontrolling device.

An advantage of the present invention is that it can be used forambulatory patients.

Another object of the invention is that it makes it possible to adjustparticle size by adding energy to the air surrounding the particles inan amount sufficient to evaporate carrier and reduce total particlesize.

Another object or the invention is that it reduces or eliminates thevariability in particle size due to variations in ambient relativehumidity and temperature by ensuring that the delivered particles are inthe range of 1-3.5 μm independent of ambient conditions. This object ofthe invention car, apply equally well to aerosol generation devices thatgenerate aerosols of liquid solutions of drug, liquid suspensions ofdrug, or dry powders of drug.

Another object is to provide a device for the delivery of aerosols whichmeasures ambient humidity via a solid state hygrometer, and/or measuresambient temperature via a temperature sensor.

A feature of the invention is that drug can be dispersed or dissolved ina liquid carrier such as water and dispersed to a patient as dry orsubstantially dry particles.

These and other objects, advantages and features of the presentinvention will become apparent to those skilled in the art upon readingthis disclosure in combination with drawings wherein like numerals referto like components throughout.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphic model showing the fraction of particles that depositin the pulmonary, tracheobronchial, and oro-pharyngeal compartments, asa function of particle diameter;

FIG. 2 is a graphic model similar to FIG. 1, showing the effect of abreath hold maneuver on lung deposition;

FIG. 3 is a schematic view of an embodiment of a air temperaturecontrolling device of the invention;

FIG. 4 is a schematic view of an embodiment of an aerosol deliverydevice of the invention;

FIG. 5 is a graph plotting the density (mg/liter) of water vapor in airversus temperature;

FIG. 6 is a graph plotting the density (mg/liter) of ethanol vapor inair versus temperature;

FIG. 7 is an overhead schematic view of the temperature controllingapparatus; and

FIG. 8 is a side schematic view of the temperature controllingapparatus.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before the present air temperature controlling device, method ofaerosolizing formulations and devices and formulations used inconnection with such are described, it is to be understood that thisinvention is not limited to the particular embodiments described, assuch heating elements, methods, devices, packages, containers andformulations may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to limit the scope of the presentinvention which will be limited only by the appended claims.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “aformulation” includes mixtures of different formulations, reference to“an aerosolized compound” includes a plurality of such compounds, andreference to “the method of treatment” includes reference to equivalentsteps and methods known to those skilled in the art, and so forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are now described. All publications mentioned herein areincorporated herein by reference to disclose and describe the specificmethods and/or materials in connection with which the publications arecited.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Definitions

The terms “portable air temperature controlling device”, “airtemperature controller” and the like refer to a self-contained devicecomprising a heating element which can be positioned in a aerosoldelivery device in a manner such that air of an aerosol created by thedevice is warmed when contacting the heating element. The devicepreferably includes a receptacle for a power source for the heating ofthe heating element, and a control circuit to monitor and control thetemperature of the heating element.

The term “receptacle” refers to a location in a portable drug deliverydevice for connecting a portable power source which power source ispreferably two or more electric cells, i.e. a battery. The airtemperature controlling device is preferably an integral part of aaerosol delivery device which together (with the power source) weighless than 1.5 kg; more preferably, less than 0.75 kg. The receptacle mayconsist of an attachment point essentially outside of the device, orpreferably an enclosed volume with a door that contains the power sourceinside the device. The receptacle preferably contains a method ofconnecting and disconnecting the means of transmitting power from thepower source to the air temperature controlling device, such aselectrical contacts.

The term “portable power source” refers to any source capable ofgenerating power which can be transferred to the heating element in theportable air temperature controlling device, and preferably is a sourceof electrical energy, more preferably stored in a chemical cell which isan electric cell—two or more electric cells combined forms a battery. Ina preferred embodiment the power source is one or more electrical cells,(i.e. a battery) which is/are sufficiently small such that when loadedinto the device the device remains easily portable, e.g., AA size, Csize or D size or smaller. Chemical reactions (especially the catalyticcombustion of butane), hand-powered generators or friction devices couldalso be used.

The term “heating element” refers to any element capable of convertingpower provided by a portable power source into heat and releasing it tothe surrounding air. In a preferred embodiment the heating element is ametal. The exact structure of the element is not critical, but it mustbe capable of transferring its heat to the air then to the aerosol overa period of from about 0.1 to about 10 seconds, more preferably about1-2 seconds. In a preferred embodiment, the heating element is coilednickel chromium or nickel copper wire, which wire is present in anamount ranging from about 1 to about 10 grams, more preferably about 2-4grams. If the source of power is a electric cell or group of electriccells (a battery), the heating element must be designed so that itsoperation is consistent with a battery which is portable (size andweight are small) and can provide enough energy over a short period oftime (e.g., one minute or less) to heat the heating element so that itholds enough energy to warm the air into which the aerosol is generatedsufficiently to evaporate the desired amount of carrier away from theparticles. For example, if the heating element is in the form of a metalwire coil, the wire can not be too thick or too thin. A nickel chromiumwire of about 26±10 gauge is preferred.

The terms “hormone,” “hormone drug,” “pharmaceutically active hormoneformulation,” “peptide used in endocrine therapy,” “peptide hormonedrug,” “peptide drug” and the like are used interchangeably herein. Ahormone drug as described herein is a peptide drug which has beenprepared in a pharmaceutically effective formulation and is useful inendocrine therapy. Specifically, a peptide drug of the type describedherein is useful for exogenously modifying the behavior of a patient'sendocrine system. Peptide drugs which are used in the present inventioninclude those listed in Table 2, it being noted that these peptidespreferably contain less than 50, more preferably less than 27, aminoacids. Drug of smaller size are preferred. Particularly useful peptidedrugs for use with the invention include leuprolide, calcitonin, andnafarelin. The devices and methods disclosed herein can be used in thecreation of an aerosol for inhalation into the lungs using anypharmaceutically active peptide. Examples of useful peptides include:

TABLE 2 Insulin (e.g. human recombinant) Insulin analogs (e.g. insulinlispro) Interferon-alpha Interferon-gamma HPTH (human parathyroidhormone) GCSF (granulocyte colony stimulating factor) GMCSF (granulocytemacrophage colony stimulating factor) Atrual natriuretic factorAngiotensin inhibitor Renen inhibitor Somatomedin FSH (folliclestimulating hormone) Tissue growth factors (TGF's) Endothelial growthfactors HGF (hepatocyte growth factor) Amylin Factor VIII VasopressinIIB/IIIA peptide antagonists

The invention is intended to cover such pharmaceutically activepeptides, which are synthetic, naturally occurring, glycosylated,unglycosylated, pegylated forms and biologically active analogs thereof.The invention can be applied to the aerosolized delivery of insulin andinsulin analogs, particularly any monomeric insulin (e.g. insulinlispro).

The terms “drug”, “pharmaceutically active drug”, and “active drug” andthe like are used interchangeably herein to refer to any chemicalcompound which, when provided to a mammal, preferably a human, providesa therapeutic effect. Preferred drugs are peptide hormones, proteinssuch as erythropoietin, peptides and the like including insulin andinsulin analogs such as insulin lispro, small molecule drugs includingmorphine, fentanyl, and the like, i.e. drugs which are commonly used andwhich are conventionally delivered by injection.

The term “treatment” is used here to cover any treatment of any diseaseor condition in a mammal, particularly a human, and includes:

(a) preventing the disease or condition from occurring in a subjectwhich may be predisposed to the disease but has not yet been diagnosedas having it;

(b) inhibiting the disease or condition, i.e. arresting its development;and/or

(c) relieving the disease or condition, i.e. causing regression of thedisease and/or its symptoms.

The term “dosing event” shall be interpreted to mean the administrationof a drug to a patient in need thereof by the intrapulmonary route ofadministration which event may encompass one or more releases of drugformulation from a drug dispensing device over a period of time of 15minutes or less, preferably 10 minutes or less, and more preferably 5minutes or less, during which period an inhalation or multipleinhalations are made by the patient and a dose of drug is released andinhaled. A dosing event shall involve the administration of drug to thepatient in an amount of about 1 μg to about 10 mg. The dosing event mayinvolve the release of from about 1 μg to about 100 mg of drug from thedevice.

The term “bulk flow rate” shall mean the average velocity at which airmoves through a channel considering that the flow rate is at a maximumin the center of the channel and at a minimum at the inner surface ofthe channel.

The term “carrier” shall mean any non-active compounds present in theformulation. The carrier is preferably a liquid, flowable,pharmaceutically acceptable excipient material which thepharmaceutically active drug is suspended in or more preferablydissolved in. Useful carriers do not adversely interact with the drug orpackaging and have properties which allow for the formation of aerosolparticles preferably having a diameter in the range of 0.5 to 15microns. The particles may be formed when a formulation comprising thecarrier and drug is forced through pores having a diameter of 0.25 to3.0 microns. Preferred carriers include water, ethanol and mixturesthereof. Other carriers can be used provided that they can be formulatedto create a suitable aerosol and do not adversely effect the drug orhuman lung tissue. The term carrier includes excipient materials whichare used with formulation for nebulizers, any powder inhalers andmetered dose inhalers or devices of the type described in U.S. Pat. No.5,709,202.

The term “inspiratory volume” shall mean a measured, calculated and/ordetermined volume of air passing a given point into the lungs of apatient assuming atmospheric pressure ±5% and a temperature in the rangeof 10° C. to 40° C.

The terms “formulation” and “liquid formulation” and the like are usedherein to describe any pharmaceutically active drug by itself or with apharmaceutically acceptable carrier. A formulation could be a powder,that may have previously been spray dried, lyophilized, milled, or thelike, and may contain a large amount of inactive ingredients such aslactose or mannitol. The formulation is preferably in flowable liquidform having a viscosity and other characteristics such that theformulation can be aerosolized into particles which are inhaled into thelungs of a patient after the formulation is aerosolized, e.g. by beingmoved through a porous membrane. Such formulations are preferablysolutions, e.g. aqueous solutions, ethanolic solutions,aqueous/ethanolic solutions, saline solutions, microcrystallinesuspensions and colloidal suspensions. Formulations can be solutions orsuspensions of drug in a low boiling point propellant or even drypowders. Dry powders tend to absorb moisture and the invention decreasesthe moisture content and makes it possible to deliver particles ofpowder which have a consistent size even when the surrounding humidityis variable.

The term “substantially dry” shall mean that particles of formulationincluding an amount of carrier (e.g. water or ethanol) which iscomparable to (in weight) or less than the amount of drug in theparticle. Preferably such particles consist essentially of only drugwith no free carrier e.g., no free water, ethanol or other liquid.

The terms “aerosol,” “particles,” “aerosol particles,” “aerosolizedformulation” and the like are used interchangeably herein and shall meanparticles of formulation comprised of pharmaceutically active drug andcarrier which are formed for aerosol delivery, e.g. upon forcing theformulation through a nozzle which nozzle is preferably in the form of aflexible porous membrane or generated using a jet or ultrasonicnebulizer. Preferably, the particles have a size in the range of 0.5micron to about 12 microns (more preferably 1-3.5 microns).

The terms “particle diameter” and “diameter” are used when referring tothe diameter of an aerosol particle and are defined as the “aerodynamicdiameter”. The “aerodynamic diameter” is the physical diameter of asphere of unit density (1 gm/cm³) that has the same terminalsedimentation velocity in air under normal atmospheric conditions as theparticle in question. This is pointed out in that it is difficult toaccurately measure the physical diameter of small particles usingcurrent technology and because the shape may be continually changing. Inaddition, the deposition of aerosol particles in the bronchial airwaysof a human subject is described by a Stokes impaction mechanism which ischaracterized by a particles aerodynamic diameter. Thus, the diameter ofone particle of material of a given density will be said to have thesame diameter as another particle of the same material if the twoparticles have the same terminal sedimentation velocity in air under thesame conditions.

The terms “ambient conditions,” “ambient temperature,” “ambient relativehumidity” refer to the conditions of the air surrounding the patient andaerosol generation device, prior to this air being entrained into thedevice and being conditioned by the temperature controller.

The term “aerosol generation device” refers to any device for forming anaerosol for delivery to a human. These devices include but are notlimited to systems that generate aerosols from liquid formulations, suchas jet or ultrasonic nebulizers, spinning top generators, devices usingan orifice or an array of orifices to form an aerosol (driven by aoscillation mechanism or not), and devices for the delivery of drypowder aerosols. Different types of aerosol delivery devices can utilizethe temperature controller components described herein.

The term “drug delivery device” refers to a self contained portabledevice for the delivery of medication by way of inhalation. The drugdelivery device preferably comprises a temperature controller component.

The term “temperature sensor” refers to an electrical component that hassome measurable, repeatable property that can be used to determine thetemperature of the component, and thus the temperature of some othersubstance which the sensor is in thermal contact with, such as a heatingelement or the surrounding air. The temperature sensor can be athermocouple, a diode, or preferably a resistance device such as athermistor or RTD.

The term “temperature coefficient of resistance” refers to the amount ofchange of the resistance of an electrical component. The temperature ofa component can be measured by measuring its resistance, assuming it hasa sufficiently large temperature coefficient of resistance over therange of temperatures of interest, the resistance changes monotonically,and its resistance as a function of temperature has previously beendetermined. The component could be a heating element, or a temperaturesensor. If the component is a heating element, the preferred alloy is anickel-iron, or similar alloy.

Device in General

An air temperature controlling device for use in conjunction with anaerosol generation device for the delivery of drugs via aerosol to thelung is disclosed. The device has a self-contained power source included(e.g. electric cells which form a battery). The drug delivery devicewill include a receptacle for the self-contained power source. Thereceptacle may hold an electrical cell or cells in the receptacle inwhich case the receptacle will include electrical contacts. The drugdelivery device preferably comprises a channel which forms an air flowpath having a first opening into which ambient air can be drawn and asecond opening from which conditioned air can be delivered to theaerosol generation device, where the driving force for the air flow ispreferably the patient's inhalation. The drug delivery device preferablycomprises a heating element which is connected to the contacts of thereceptacle for the self-contained power source. In the preferredembodiment, the power source is a battery and the contacts areelectrical contacts. However, the power source may be a container of aliquid substance such as butane or propane, in which case the contactswould be a means of connecting the power source to the means ofdelivering the liquid to the heating element.

The heating element is positioned in a manner such that air flowingthrough the air flow path contacts the heating element and is warmed. Inthe case of a liquid formulation, the air is warmed to the extent thatit can hold essentially all of the carrier in the particles after it hasbeen cooled by the process of carrier evaporation (see FIG. 2), underall ambient conditions expected to be encountered in the lifetime of thedevice. In the case of a dry powder inhaler, the air is warmed to theextent that particle growth is inhibited at all ambient conditionsexpected to be encountered in the lifetime of the device. Preferably,the air is warmed in an amount such as to result in the evaporation of50% or more of any liquid carrier and more preferably warmed to theextent to evaporate substantially all the compound liquid carrierleaving the particles dry, i.e. leaving the particles in a form whereany liquid carrier such as water and/or ethanol which is not complexedwith or bound to the drug has been evaporated away. The device is ahand-held, self-contained device which has a total weight of 1 kilogramor less in its loaded form.

The aerosol generation device to be combined with the present inventionis preferably loaded with a disposable drug container of the typedisclosed within U.S. Pat. No. 5,497,763 issued Mar. 12, 1996—see alsoU.S. Pat. No. 5,544,646 issued Aug. 13, 1996, U.S. Pat. No. 5,660,166issued Aug. 26, 1997, and U.S. Pat. No. 5,718,222 issued Feb. 17, 1998,all of which are incorporated herein by reference to disclose a aerosolgeneration device and a disposable container for containing a drug foraerosolized delivery.

Different embodiments of the air temperature controlling device of thepresent invention may contain a variety of different power sourcesprovided the power source is self-contained allowing the device to behand held and portable. The power source may be a container of a liquidsuch as butane or propane, or is more preferably in the form of anelectric cell or a plurality of electric cells, i.e. a battery.Typically, the receptacle holds a battery securely in place and haselectrical metal contacts to contact a positive and negative end of anelectric cell or battery. Different types of batteries can be usedincluding rechargeable batteries. It is preferable to use standard sizecells, more preferably AA (or similar) size cells. Specifically, thepresent invention has been developed so that it is very light weight andportable and can provide the necessary warming by power received from afew AA size electric cells. However, the invention is intended toencompass portable devices which include somewhat larger electric cells,e.g. D size electric cells or smaller.

The power source is brought into contact with electrical contacts on thereceptacle thereby powering the drug delivery device. The electricalcontacts of the receptacle lead to the heating element which is the mostimportant aspect of the present invention and to other components of thedevice which require power.

The utility of the invention can be heightened by improving theefficiency of the air temperature controlling device, thus minimizingthe number of batteries (and thus the size and weight of the drugdelivery device), and maximizing the number of doses delivered beforethe power source needs to be replaced or recharged. The efficiency ofthe air temperature controller can be increased by insulating the wallsof the air path, thus minimizing the amount of heat lost during thepreheat and storage phases of the cycle. Additionally, a valving meanscan be used to only deliver conditioned air during the period of aerosolgeneration, and deliver ambient air during the parts of an inhalationprior to and following aerosol generation, thus minimizing the amount ofpreheating of the heating element required, and saving heat in theheating element for subsequent inhalations.

The heating element may take a variety of different forms but ispreferably in the form of a coiled wire and most preferably in the formof a nickel chromium wire which is about 16 to 36 gauge and mostpreferably 26 gauge. Alternatively, the heating element may be formed ofstamped metal of similar composition. The composition and physicalstructure of the heating element must be carefully designed in order toprovide a heating element which can quickly store energy in the form ofheat and thereafter quickly release that stored heat energy to thesurrounding air. In addition, the heating element must be such that itcan perform the heat storage and release tasks when being powered by asmall power source such as a few AA electric cells.

The heating element must be designed so as to provide energy in therange of about 150 to 350 joules, most preferably about 250 joules tothe surrounding air in a relatively short period of time, i.e. about 0.5to 4.0 seconds, more preferably 1-2 seconds. In order to produce such aheating element and power source wherein the device remains small andportable it has been found that it is not possible to design the systemwherein the energy is provided in real time (i.e. at the same time asthe aerosol is generated) from an electrical power source, due to theinternal impedance of existing battery technologies. Accordingly, thepower source is used to preheat the heating element which acts as a heatsink before the energy is delivered. Thus, the concept is similar to theconcept of charging a capacitor in order to operate a flash on a camera.In the same manner the heat sink or heating element of the inventionacts as a “heat capacitor” and stores energy from the power source untilsufficient energy is stored and then delivers that stored energy to thesurrounding air at a rate well beyond that which would be possible withthe power source itself. Alternatively, the power may be stored in anelectrical capacitor, and then delivered to the heating element from thecapacitor during aerosol generation. State of the art of high capacity,high discharge rate capacitors should be used. When the patient inhalesthrough the device air is drawn over the heating element and energy istransferred to the air, warming the air. The precise amount of airwarmed and the amount which the air is warmed to can be changed usingdifferent components in the temperature controlling device, or bychanging the amount of preheating of the heating element prior toaerosol generation.

Optimum performance can be achieved by limiting the density of theaerosol generated. For example, it is typical to aerosolize a volume offormulation in the range of about 1 microliter to about 100 microlitersper liter of inhaled air. By making the formulation more concentratedless energy is required per mass of drug delivered in order to evaporateaway the carrier and produce smaller particles. However, when theformulation is more dilute the heat energy added can have a greatereffect on reducing particle size. More specifically, since the moredilute solution will contain a larger amount of carrier the heatingelement can have a larger effect on reducing the particle size.

The invention preferably includes a control circuit to measure andcontrol the temperature of the heating element. This is required tooptimize the amount of preheating when, for example, the batteries arenear the end of there useful lifetime. It could also monitor thetemperature and relative humidity of the ambient air, and vary theamount of preheating accordingly. The control circuit may be an analogcircuit, digital circuit, or hybrid analog/digital circuit, andpreferably includes a microprocessor. The control circuit of theinvention can be designed to add the desired amount of heat depending onthe amount of carrier in the aerosol particles and (1) the density(number of aerosol particles per liter of air) of the generated aerosol(2) the size of the particles initially as well as (3) the size of theparticles desired after the carrier has been evaporated away. Thecontrol of the aerosol generation device may be integrated in the samecircuit, and may, for example, share the microprocessor whichmicroprocessor may be the type disclosed in U.S. Pat. Nos. 5,404,871,5,542,410 and 5,655,516.

The device may include a hygrometer for measuring ambient humidityand/or a temperature sensor for measuring ambient temperature.Information collected by the hygrometer and/or temperature sensor issupplied to the control circuit which determines the amount of energy tobe added to the surrounding air by the heating element. As the humidityincreases additional energy may be necessary in order to evaporatecarrier away from the particles. In the preferred embodiment, theheating element warms the air sufficiently to evaporate essentially allof the carrier over the range of ambient conditions expected in thelifetime of the device, thus obviating the need for relativehumidity/ambient temperature sensor.

In general, when the heating element is in the form of a 26 gauge nickelchromium wire the heating element has a weight of approximately 3 to 7grams, more preferably 5 grams. The heating element preferably iscapable of generating energy in an amount of about 20 joules or more,and generally generates energy in the amount of about 20 to 10 joulesper 10 microliters of formulation.

It is pointed out that the device of the present invention can be usedto, and actually does, improve the efficiency of drug delivery. However,this is a secondary feature. The primary feature is the improvedreproducibility of the emitted dose and particle size over the range ofambient conditions likely to be encountered while using the device. Theair temperature controlling device aids in improving repeatability bykeeping the delivered aerosol particles inside of a closely controlleddiameter range.

The methodology of the invention may be carried out using a portable,hand-held, battery-powered device using a microprocessor as disclosed inU.S. Pat. No. 5,404,871, issued Apr. 11, 1995 and U.S. Pat. No.5,450,336, issued Sep. 12, 1995 incorporated herein by reference. Thecontrol circuit can be additionally designed to monitor inhalation flowrate, total inhaled volume, and other parameters, and commencegeneration of aerosol at a predefined optimal point during theinhalation. In accordance with the system the drug is included in anaqueous formulation which is aerosolized by moving the formulationthrough a porous membrane. The pre-programmed information is containedwithin nonvolatile memory which can be modified via an external device.In another embodiment, this pre-programmed information is containedwithin a “read only” memory which can be unplugged from the device andreplaced with another memory unit containing different programminginformation. In yet another embodiment, a microprocessor, containingread only memory which in turn contains the pre-programmed information,is plugged into the device. For each of these embodiments, changing theprogramming of the memory device readable by a microprocessor willchange the behavior of the device by causing the microprocessor to beprogrammed in a different manner. This is done to accommodate differentdrugs for different types of treatment.

The drug which is released to the patient may be in a variety ofdifferent forms. For example, the drug may be an aqueous solution ofdrug, i.e., drug dissolved in water and formed into small particles tocreate an aerosol which is delivered to the patient. Alternatively,liquid suspensions or dry powders may be used. Alternatively, the drugmay be in a solution wherein a low-boiling point propellant is used as asolvent.

Some peptide drugs are subject to being degraded more quickly when insolution such as an aqueous solution. Preferably such drugs are packagedin a dry form and mixed with water prior to administration. A dualcompartment container for carrying out such is shown in U.S. Pat. No.5,672,581. Alternately, the drug is kept in the form of a dry powderwhich is intermixed with an airflow in order to provide for delivery ofdrug to the patient.

Regardless of the type of drug or the form of the drug formulation, itis preferable to create aerosol particles having a size in the range ofabout 1 to 3.5 microns. By creating particles which have a relativelynarrow range of size, it is possible to further increase the efficiencyof the drug delivery system and improve the repeatability of the dosing.Thus, it is preferable that the particles not only have a size in therange of 1.0 to 3.5 microns but that the mean particle size be within anarrow range so that 80% or more of the particles being delivered to apatient have a particle diameter which is within ±50% of the averageparticle size, preferably ±25% of the average particle size. The heatingelement is particularly useful in reducing particle size and in creatinga aerosol with uniform sized particles.

The amount of drug delivered to the patient will vary greatly dependingon the particular drug being delivered. In accordance with the presentinvention it is possible to deliver a wide range of drugs. For example,drugs delivered could be drugs which have a systemic effect e.g.leuprolide, insulin and analogs thereof including monomeric insulin, ormorphine; or a local effect in the lungs e.g. Activase, albuterol, orsodium cromoglycate.

TABLE 3 Useful Peptide Hormone Drugs Amino Compound acids Somatostatin 6Oxytocin 9 Desmopressin 9 LHRH 10 Nafarelin 10 Leuprolide 11 ACTH analog17 Secretin 27 Glucagon 29 Calcitonin 32 GHRH 40 Growth hormone 191

Having generally described the invention above reference is now made tothe figures in order to more particularly point out and describe theinvention.

FIG. 1 is a graph of deposition fraction versus particle diameter withthe particle diameter being the aerodynamic diameter of a particlehaving a density of 1 gram per square centimeter with the scale beingread in terms of increasing particle diameter in units of μm. Theaerodynamic diameters are plotted versus the deposition fraction in thelungs. For each of the different lines shown on the graph the data isprovided for the deposition fraction in the different areas of the lungand for the total deposition. As can be seen on the graph theoro-pharyngeal deposition which is basically in the back of the throatoccurs for particles which are somewhat large. Specifically, as theparticle size increases to an aerodynamic diameter above 10 μm nearlyall of the particles are deposited in the oro-pharyngeal area. It ispointed out that the graph does not represent actual data but isbelieved to be a fairly accurate representation of what occurs duringintrapulmonary drug delivery particularly where the patient being testedis breathing at a rate of 15 breaths per minute with a 750 ml tidlevolume.

FIG. 2 is similar to FIG. 1 and is a plot of aerodynamic diameter versusfractional deposition. In FIG. 2 the graphs show “p” which is pulmonarydeposition with “bh” breath holding and without breath holding. Similarto FIG. 1, this graph represents theoretical and not actual data. As canbe seen in the graph the breath holding technique does improve theamount of pulmonary deposition. Particularly when the particles have anaerodynamic diameter less than 5 μm.

FIGS. 1 and 2 together clearly indicate the importance of the presentinvention. Specifically, the figures indicate that the area of the lungwhich particles deposit in and the percentage of the particles whichdeposit there is substantially effected by the aerodynamic diameter ofthe particles. In that the present invention makes it possible toprovide for consistent aerodynamic particle size the invention providesfor consistent delivery of the particles to particular areas of the lungand therefore repeatable dosing of a patient.

FIG. 3 schematically shows an embodiment of the air temperaturecontroller. Battery 1 is electrically connected to heating element 2through relay 3. The relay 3 may be a mechanical, or preferably a solidstate relay. Relay 3 is controlled by control circuit 6 which includesmicroprocessor 4. Temperature sensor 5 is in thermal contact withheating element 2, and is monitored by control circuit 6. Optionalambient relative humidity sensor 7 and ambient temperature sensor 8 arealso monitored by control circuit 6. Ready light 9 (see FIG. 4) iscontrolled by microprocessor 4. Power for the entire system is suppliedby battery 1. The heating element 2 is positioned in air path 11 formedby the cylinder 12, leading to aerosol generation device 13.

FIG. 4 is an embodiment of an aerosol drug delivery device utilizing theinvention. The device 40 shown in FIG. 4 is loaded with a disposablepackage 14. To use the device 40 a patient inhales air from themouthpiece 18 through the opening 25 in the cylinder 12. The air drawnin through the opening 25 (and optionally the desiccator 24) flowsthrough the flow path 11 of the channel 12. The disposable package 14 iscomprised of a plurality of disposable containers 15. Each container 15includes a drug formulation 16 and is covered by a nozzle array orporous membrane 17. The heating element 2 is located in the flow path11. The heating element 2 is preferably positioned such that all or onlya portion of the air flowing through the path 11 will pass by theheating element 2, e.g., flow vent flaps can direct any desired portionof air past the heating element 2. The relay 3 (see FIG. 3) ispreferably closed for 30 sec or less prior to inhalation and openedafter drug delivery to conserve power.

The device 40 may include a mouth piece 18 at the end of the flow path11. The patient inhales from the mouth piece 18 which causes aninspiratory flow to be measured by flow sensor 19 within the flow pathwhich path may be, and preferably is, in a non-linear flow pressurerelationship. This inspiratory flow causes an air flow transducer 20 togenerate a signal. This signal is conveyed to a microprocessor 4 whichis able to convert the signal from the transducer 20 in the inspiratoryflow path 11 to a flow rate in liters per minute. The microprocessor 4can further integrate this continuous air flow rate signal into arepresentation of cumulative inspiratory volume.

When the device is turned on by the user, the microprocessor 4 will senda signal to send power from the power source 1 (which is preferably asmall battery) to the air temperature controller 2 and will continue topreheat the temperature controller 2 until it reaches a predeterminedtemperature. The preheat temperature can be preprogrammed based on suchinformation as the particle size generated, the particle size desired,the formulation concentration, and other parameters. The microprocessor4 may also adjust the preheat temperature to optimize each deliverybased on the ambient conditions, using information from the optionalhygrometer/temperature sensor 7. The microprocessor 4 also sends asignal to an actuator 22 which causes the mechanical means (e.g., thepiston 23) to force drug from a container 15 of the package 14 into theinspiratory flow path 11 of the device 40 where the aerosol is formedand entrained into the inhalation air and delivered into the patient'slungs.

When the formulation 16 includes water as all or part of the carrier itmay also be desirable to include a desiccator 24 within the flow path11. The desiccator 24 is preferably located at the initial opening 25but maybe located elsewhere in the flow path 11 prior to a point in theflow path when the formulation is fired into the flow path in the formof aerosol particles. By drawing air through the desiccator 24 watervapor within the air is removed in part or completely. Therefore, onlydried air is drawn into the remainder of a flow path. Since the air iscompletely dried, water carrier within the aerosol particles will morereadily evaporate. This decreases the energy needs with respect to thetemperature controller 2. The desiccator material can be any compoundwhich absorbs water vapor from air. For example, it may be a compoundselected from the group consisting of P₂O₅, Mg(ClO₄), KOH, H₂SO₄, NaOH,CaO, CaCl₂, ZnCl₂, and CaSO₄.

Device Operation

The operation of the device 40 can be understood by reference to acombination of FIGS. 3 and 4. Referring to FIG. 3 when the relay 3 isclosed the heating element 2 begins to heat. In addition to the heatingelement 2 present within the flow path 11 the flow path may also includea humidity sensor 7, temperature sensor 8 and electronic airflow sensor26. When a patient (not shown) inhales through the mouth piece 18 airflows in through the opening 25 and is sensed by the air flow sensor 26after being electronically converted by the transducer 20. The signalflows along the electrical connection 26 to the microprocessor 4. Thecombination of the control circuit 6 and the microprocessor 4 send asignal back through the connection 26 to the heating element 2 which ispowered by the battery 1. The amount of power to be supplied to theheating element 2 is also tempered, to a degree, by information receivedfrom the humidity sensor 7 and temperature sensor 8 which information isconsidered by the microprocessor 4. When the heating element 2 reachesthe correct temperature and the air flow sensor 26 determines that theinspiratory flow rate and inspiratory volume are at the desired pointthe microprocessor 4 sends a signal to the actuator 22. The actuator 22may be any type of device such as a selenoid which then moves themechanical release member 21 so that the piston 23 is released. Thepiston 23 is forced upward by a spring or other biasing means 28. Thebiasing means may be held within a grip 29 which can be easily held bythe user. Where the microprocessor 4 sends the signal through the line30 to the actuator 22 the spring is released and a container 15 iscrushed and the formulation 16 inside the container is released throughthe membrane 17.

When the container 15 is present in the drug release position below thepiston 23 the container 15 may have vibrating devices 31 and 32positioned on either side or a single device surrounding the container15. The vibrating device(s) may be actuated by the microprocessor 4sending a signal through the connection 23. Empty containers 15 areshown to the left of the drug actuation point. In a preferred embodimentof the methodology a new container and new porous membrane are used foreach drug release. By using a new porous membrane each time clogging ofthe porous membranes is avoided. Further, possible contamination of theformulation 16 present in the container 15 is avoided.

Those skilled in the art will recognize that a variety of differentcomponents could be used in place of some of the components shown withinFIGS. 3 and 4. For example, rather than including a piston biased by aspring it would be possible to utilize a rotating cam. Further, othercomponents of the invention, although preferred, are not required. Forexample, components such as the humidity sensor 7 and temperature sensor8 could be eliminated without substantial impairment of operability bysimply adjusting the amount of energy supplied to the heating element 2so as to compensate for any humidity or temperature which might beencounter by the user. However, such would acquire the use ofunnecessary amounts of power in some situations.

When the air temperature controller shown in FIG. 3 is activated,microprocessor 4 closes relay 3, commencing the preheat of heatingelement 2. Microprocessor 4 monitors temperature sensor 5 until heatingelement 2 reaches a temperature that is determined by ambient conditionsas measured by optional ambient relative humidity sensor 7 and/orambient temperature sensor 8, or preferably a temperature that has beenpreviously determined to be sufficient for all ambient conditions to beseen in the normal operation of the device. When this temperature isreached, the microprocessor opens relay 3 to inhibit further heating,and lights the ready light 9 to signal to the patient that the device isready for a dosing event. The microprocessor continues to monitortemperature sensor 7 and opens and closes relay 3 as required tomaintain the desired temperature until the patient inhales from thedevice.

Energy for Evaporation

FIG. 5 is a graph which can be used in calculating the amount of energyneeded to control the size of delivered droplets by controlling theamount of evaporation of carrier from the aerosolized droplets. Thegraph of FIG. 5 contains two types of information, the density ofevaporated water vs. temperature and relative humidity, and the coolingof the air as the water evaporates. The four lines that show a rapidincrease with temperature portray the density of water vapor in air, at25, 50, 75, and 100% relative humidity. The 100% relative humidity curverepresents the maximum number of milligrams of water that can beevaporated per liter of air. The diagonal lines show the temperaturechange of the air as the water droplets evaporate (hereafter called theair mass trajectory curves). As the evaporation proceeds, the densityand temperature will change by moving parallel to these curves. Tocalculate these curves, air density of 1.185 grams/liter, air specificheat of 0.2401 calories/gram, and water latent heat of vaporization of0.583 cal/mg were assumed. It is also assumed that the evaporationprocess is adiabatic, i.e. there is no heat removed from or supplied tothe air from other sources such as the walls of the device. These valuesimply that a liter of air will cool 2 degrees Celsius for everymilligram of water evaporated, i.e. evaporating 10 micro-liters willcool a liter of air 20 degrees Celsius.

FIG. 5 can be used to calculate the amount of preheating needed toevaporate all or substantially all of the carrier in the aerosolparticles. As an example, assume the initial ambient conditions are 25°C. and 50% relative humidity. Further, assume that one wants toevaporate 10 μl (10 mgs) of water from an aqueous drug solution.Finally, assume the final relative humidity is 75%. Under theseconditions the aqueous carrier would not in general evaporatecompletely. More specifically, the final particles would containapproximately equal amounts of drug and water. To calculate the amountof energy to add for this delivery maneuver, refer to FIG. 5. Locate thepoint corresponding to 25° C. and 50% relative humidity. Move up by 10milligrams, the amount of water to be evaporated. Now move to the leftuntil the 75% RH curve is crossed. This occurs at about 29° C. Theseconditions (75% RH and 29° C.) represent the condition of the air asdelivered to the patient. However, still more energy must be added tomake up for the cooling of the air as the water evaporates. To calculatethis amount of heat, move parallel to the air mass trajectory curves(downward and to the right) until the initial ambient water vapordensity is reached, at approximately 47° C. Thus, sufficient heat towarm the air by 22° C. must be added to achieve near completeevaporation.

FIG. 6 includes similar information with respect to ethanol which can beused in a similar manner. A preferred embodiment of the inventioncomprises a microprocessor programmed to calculate the amount of energyneeded for the formulation being aerosolized with consideration to thesurrounding temperature and humidity being accounted for. In a preferredembodiment, containers of formulation loaded into the device are labeledin a manner which is read by the device which then considers the size ofthe formulation dose to be aerosolized and the amount of liquid to beevaporated.

The evaporation and growth rates of aqueous droplets is a function oftheir initial diameter, the amount of drug dissolved therein(concentration) and the ambient relative humidity and temperature. Thedetermining factor is whether the water vapor concentration at thesurface of the droplet is higher or lower than that of the surroundingair. Because the relative humidity at the surface of a particle (i.e.droplet of aerosolized formulation) is close to 100% for mostformulations of interest, evaporation will occur under most ambientconditions until the rising humidity of the air equals the decreasinghumidity at the surface of the droplet. A five micron droplet willevaporate to a 1 micron dry particle in 0% humidity in less than 20 ms.

When administering drug using the inhalation device of the presentinvention, the entire dosing event can involve the administration ofanywhere from 10 μl to 1,000 ml of drug formulation, but more preferablyinvolves the administration of approximately 30 μl to 200 μl of drugformulation. Very small amounts of drug (e.g., nanogram or largeramounts) may be dissolved or dispersed within a pharmaceuticallyacceptable, liquid, excipient material to provide a liquid, flowableformulation which can be readily aerosolized. The container will includethe formulation having drug therein in an amount of about 10 μg to 300mg, more preferably about 1 mg. The large variation in the amounts whichmight be delivered are due to different drug potencies and differentdelivery efficiencies for different devices, formulations and patients.

System Specification Envelope

The following information is provided to specify an approximate envelopefor the design of the temperature controlling system.

-   A. Batteries    -   Chemistry: Nickel Cadmium, Nickel Metal-Hydride, Lithium-Ion,        Lithium-Metal,    -   Lithium Polymer    -   Voltage: 1 Volt to 20 Volt    -   Internal, Impedance: less than 0.1Ω per cell    -   Number of cells: 1 to 10-   B. Heating Element    -   Total Heat Capacity: 0.2 J/C to 4.35 J/C    -   Surface Area: 10 cm² to 150 cm²    -   Electrical Resistance: 0.5Ω to 5Ω    -   Mass: 1-10 grams-   C. Control Relay    -   Type: Solid State, Mechanical, Transistor-   D. Temperature Sensors    -   Types: Resistance, Thermocouple, Diode

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use various constructs and perform the various methods of thepresent invention and are not intended to limit the scope of what theinventors regard as their invention nor are they intended to representor imply that the embodiments described below are all on the onlyembodiments constructed or tested. Efforts have been made to ensureaccuracy with respect to numbers used (e.g., amounts, concentrations,particular components, etc.) But some deviations should be accountedfor.

Example 1

A preferred embodiment of a temperature controller system 41 is shown inFIGS. 7 and 8. The system is comprised of wire 42 of total length of 130inches. The 2.2 gram wire is split into six coils 43, 44, 45, 46, 47 and48, each having approximately 8.4Ω resistance. Each 8.4Ω coil is thensplit in half forming coils 43′, 44′, 45, 46′, 47′ and 48′, making atotal of 12 coils. The twelve coils are then split into two banks of sixcoils each that are staggered as shown in FIG. 7 which depicts theirarrangement. Current flow is shown in FIG. 8 with air flow shown in FIG.7.

The heating element is placed inside a flow channel (11 shown in FIG. 4)(dimensions 3 cm×2 cm×1.5 cm) that is open at one end to the air, andthe other end open to the aerosol generation device. The totalelectrical resistance of the temperature controller is ˜1.6Ω (1.4Ω forheating element coils and ˜0.2Ω for various electrical connections). Athermocouple is soldered onto one of the coils to monitor thetemperature. The coils are heated until they reach a pre-specifiedtemperature and then maintained at that temperature until activation ofthe aerosol generation device.

To power the system, ten AA-sized Nickel Metal-Hydride cells (or less,e.g., four, six, seven or eight) are connected in series to give abattery voltage of 18 7.2 V. The cells each have a capacity of 1.3 Ahr.

Example 2

In another embodiment (not shown in the figures) the heating element isa 24 gauge wire of a nickel-copper alloy, wound in a conical coil orseries of coils. The axis of the cone lies along the center of the airflow path. The temperature of the coil is monitored by a platinum RTD,which is attached to the heating element. The heating element consistsof wire of total length of 80 inches. The 3.6 grams of wire is splitinto four conical coils, each having approximately 0.35Ω resistance. Thefour coils are wired in series, for a total resistance of 1.4 Ω.

The heating element is placed inside a cylindrical flow channel(dimensions 0.875″ diameter, 1.5″ long) that is open at one end to theair, and the other end open to the aerosol generation device.

To power the system, ten or less (particularly seven) AA-sized Nickelcadmium cells are connected in series to give a battery voltage of ˜8.4V. The cells each have a capacity of 1.3 Ahr.

The invention as shown and described is considered to be the one of themost practical and preferred embodiments. It is recognized, however,that the departures may be made therefrom which are within the scope ofthe invention and that obvious modifications will occur to one skilledin the art upon reading this disclosure.

1. A method, comprising: aerosolizing a liquid formulation comprised ofa pharmaceutically active drug; supplying the current from a batteryhaving a physical sign equivalent to or smaller than two standard D sizeelectric cells; heating the aerosol by application of the current fromthe battery to a wire coil comprising copper and a metal chosen fromchromium and iron, the wire having a total heat capacity of about 0.2 to4.35 J/° C. and a gauge in a range of from about 16 to about 36 andweighting from about 0.5 gram to about 10 grams and having a surfacearea of about 10 cm².
 2. The method of claim 1, further comprising:drawing the aerosol through a channel comprising an air flow path and anopening into which air is inhaled.
 3. The method of claim 2, furthercomprising: sensing ambient conditions and adjusting current suppliedbased on sensed ambient conditions.
 4. A drug delivery device,comprising: a channel comprising an air flow path, a first opening intowhich air can be inhaled and a second opening comprising a mouthpiecefrom air can be drawn; a heating element comprising a wire coil with atotal heat capacity of about 0.2 to 4.35 J/° C. and having a mass ofabout 0.5 gram to about 10 grams and a surface area of about 10cm² toabout 150 cm², and a resistance in a range of from about 0.5 ohm toabout 5 ohms the heating element positioned in the flow path of thechannel.
 5. The device of claim 4, wherein the heating element has amass of about 2 to 4 grams.
 6. The device of claim 4, furthercomprising: a portable source of power capable of supplying sufficientpower to the heating element, over a period of less than or equal to oneminute to enable the heating element to deliver about 150 to 350 Wattsof energy to surrounding air in about 0.5 to 4.0 seconds.
 7. The deviceof claim 6, where the portable power source comprises a battery capableof supplying a voltage within the range of about 1 to 20 Volts.
 8. Thedevice of claim 4, wherein the heating element is configured to deliverabout 150 to 350 Watts of energy to surrounding air in about 0.5 to 4.0seconds.
 9. The device of claim 8, wherein the heating element isconfigured to deliver about 250 Watts of energy to surrounding air inabout 1 to 2 seconds.
 10. The device of claim 4, wherein the heatingelement comprises nickel chromium wire and has a mass of about 3 to 7grams.
 11. The device of claim 10, wherein the heating element has amass about 5 grams.
 12. The device of claim 4, wherein the heatingelement is capable of generating at least 20 joules of heat energy whenconnected with a portable power source over a period of less than orequal to one minute.